Chronic airway infections with Pseudomonas aeruginosa claim the lives of the vast majority of cystic fibrosis (CF) patients. Once infection is established patients suffer frequent disease flares known as pulmonary exacerbations. During exacerbations, increased lung inflammation and injury produce worsening pulmonary function, and marked respiratory and systemic symptoms. While some flares produce transient illness, one out of four causes permanent lung function decline. The cumulative effect of these events produce respiratory failure and death, typically in the third decade of life. Unfortunately, the mechanisms that produce exacerbations remain unknown, and new treatments have been difficult to develop. Here we exploit the infrastructure of an ongoing clinical trial, and new findings about genetic diversity within infecting P. aeruginosa populations as tools to study exacerbation mechanisms. Most CF infections are clonal, meaning that the infecting population is composed of the progeny of a single isolate. In preliminary studies, we found that infecting P. aeruginosa strains evolve to produce genetically diverse (but clonally-related) bacterial populations within the host. Furthermore, evolved bacterial subpopulations differ in traits known to affect host inflammatory and injury responses. The presence of subpopulations that elicit markedly different host responses could have a major effect on disease manifestations, as our preliminary data shows that flares are associated with marked changes in infecting population composition. We will build on these findings to test the hypothesis that at the onset of exacerbations, changes in the composition of infecting P. aeruginosa populations elicit host responses leading to lung inflammation and injury. The parent clinical trial presents an unusual opportunity to test this hypothesis in human subjects.